Ohashi Emi, Kogai Takahiko, Kagechika Hiroyuki, Brent Gregory A
Molecular Endocrinology Laboratory, VA Greater Los Angeles Healthcare System, Department of Medicine, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California 90073, USA.
Cancer Res. 2009 Apr 15;69(8):3443-50. doi: 10.1158/0008-5472.CAN-08-3234. Epub 2009 Apr 7.
Iodide uptake in the thyroid and breast is mediated by the sodium/iodide symporter (NIS). NIS activation is used for radioiodide imaging and therapeutic ablation of thyroid carcinoma. NIS is expressed in >70% of breast cancers but at a level insufficient for radioiodine treatment. All-trans retinoic acid (tRA) induces NIS gene expression and functional iodide uptake in human breast cancer cell lines and mouse breast cancer models. tRA usually regulates gene expression by direct interaction of RA receptor (RAR) with a target gene, but it can also act through nongenomic pathways. We report a direct influence of tRA treatment on the phosphoinositide 3-kinase (PI3K) signal transduction pathway that mediates tRA-induced NIS expression in MCF-7 breast cancer cells. MCF-7 cells express all three RAR isoforms, alpha, beta, and gamma, and RXRalpha. We previously identified RARbeta and RXRalpha as important for NIS induction by tRA. Treatment with LY294002, the PI3K inhibitor, or p85alpha knockdown with siRNA abolished tRA-induced NIS expression. Immunoprecipitation experiments and glutathione S-transferase pull-down assay showed a direct interaction between RARbeta2, RXRalpha, and p85alpha. RA also induced rapid activation of Akt in MCF-7 cells. Treatment with an Akt inhibitor or Akt knockdown with siRNA reduced NIS expression. These findings indicate that RA induction of NIS in MCF-7 cells is mediated by rapid activation of the PI3K pathway and involves direct interaction with RAR and retinoid X receptor. Defining these mechanisms should lead to methods to further enhance NIS expression, as well as retinoid targets that influence growth and differentiation of breast cancer.
甲状腺和乳腺中的碘摄取由钠/碘同向转运体（NIS）介导。NIS激活用于甲状腺癌的放射性碘成像和治疗性消融。NIS在70%以上的乳腺癌中表达，但水平不足以进行放射性碘治疗。全反式维甲酸（tRA）可诱导人乳腺癌细胞系和小鼠乳腺癌模型中的NIS基因表达及功能性碘摄取。tRA通常通过维甲酸受体（RAR）与靶基因的直接相互作用来调节基因表达，但它也可以通过非基因组途径发挥作用。我们报道了tRA处理对磷酸肌醇3激酶（PI3K）信号转导通路的直接影响，该通路介导了tRA诱导的MCF-7乳腺癌细胞中NIS的表达。MCF-7细胞表达所有三种RAR亚型，即α、β和γ，以及RXRα。我们之前确定RARβ和RXRα对tRA诱导NIS很重要。用PI3K抑制剂LY294002处理或用siRNA敲低p85α可消除tRA诱导的NIS表达。免疫沉淀实验和谷胱甘肽S-转移酶下拉分析表明RARβ2、RXRα和p85α之间存在直接相互作用。RA还可诱导MCF-7细胞中Akt的快速激活。用Akt抑制剂处理或用siRNA敲低Akt可降低NIS表达。这些发现表明，RA在MCF-7细胞中诱导NIS是由PI3K通路的快速激活介导的，并且涉及与RAR和视黄酸X受体的直接相互作用。确定这些机制应能带来进一步增强NIS表达的方法，以及影响乳腺癌生长和分化的类视黄醇靶点。
